Diagnostic Strategy Using Color Doppler Ultrasound of Temporal Arteries in Patients With High Clinical Suspicion of Giant Cell Arteritis : A Prospective Cohort Study.

BACKGROUND: Giant cell arteritis (GCA) is the most prevalent systemic vasculitis in people older than 50 years. Any delay in diagnosis impairs patients' quality of life and can lead to permanent damage, particularly vision loss. OBJECTIVE: To evaluate a diagnostic strategy for GCA using color Doppler ultrasound of the temporal artery as a first-line diagnostic test, temporal artery biopsy (TAB) as a secondary test, and physician expertise as the reference method. DESIGN: Prospective multicenter study with a 2-year follow-up. (ClinicalTrials.gov: NCT02703922). SETTING: Patients were referred by their general practitioner or ophthalmologist to a physician with extensive experience in GCA diagnosis and management in one of the participating centers: 4 general and 2 university hospitals. PATIENTS: 165 patients with high clinical suspicion of GCA, aged 79 years (IQR, 73 to 85 years). INTERVENTION: The diagnostic procedure was ultrasound, performed less than 7 days after initiation of corticosteroid therapy. Only ultrasound-negative patients underwent TAB. MEASUREMENTS: Bilateral temporal halo signs seen on ultrasound were considered positive. Ultrasound and TAB results were compared with physician-diagnosed GCA based on clinical findings and other imaging. RESULTS: Diagnosis of GCA was confirmed in 44%, 17%, and 21% of patients by ultrasound, TAB, and clinical expertise and/or other imaging tests, respectively. Their diagnosis remained unchanged at 1 month, and 2 years for those with available follow-up data. An alternative diagnosis was made in 18% of patients. The proportion of ultrasound-positive patients among patients with a clinical GCA diagnosis was 54% (95% CI, 45% to 62%). LIMITATION: Small sample size, no blinding of ultrasound and TAB results, lack of an objective gold-standard comparator, and single diagnostic strategy. CONCLUSION: By using ultrasound of the temporal arteries as a first-line diagnostic tool in patients with high clinical suspicion of GCA, further diagnostic tests for patients with positive ultrasound were avoided. PRIMARY FUNDING SOURCE: Tender "Recherche CH-CHU Poitou-Charentes 2014."

Heterogeneity of Mismatch Repair Status and Microsatellite Instability between Primary Tumour and Metastasis and Its Implications for Immunotherapy in Colorectal Cancers.

Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of metastatic colorectal cancers (mCRCs) with a major therapeutic impact for immune checkpoint inhibitor (ICI) use. We conducted a multicentre study including all consecutive patients with a dMMR/MSI mCRC. MSI status was determined using the Pentaplex panel and expression of the four MMR proteins was evaluated by immunohistochemistry (IHC). The primary endpoint was the rate of discordance of dMMR/MSI status between primary tumours and paired metastases. We included 99 patients with a dMMR/MSI primary CRC and 117 paired metastases. Only four discrepancies (3.4%) with a dMMR/MSI primary CRC and a pMMR/MSS metastasis were initially identified and reviewed by expert pathologists and molecular biologists. Two cases were false discrepancies due to human or technical errors. One discordant case could not be confirmed due to the low level of tumour cells. The last case had a confirmed discrepancy with a dMMR/MSI primary CRC and a pMMR/MSS peritoneal metastasis. Our study demonstrated a high concordance rate of dMMR/MSI status between primary CRCs and their metastases. The analysis of one sample, either from the primary tumour or metastasis, with consistent dMMR and MSI status seems to be sufficient prior to treatment with ICI.

HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability.

Determination of microsatellite instability (MSI) using molecular test and deficient mismatch repair (dMMR) using immunohistochemistry (IHC) has major implications on colorectal cancer (CRC) management. The HSP110 T 17 microsatellite has been reported to be more monomorphic than the common markers used for MSI determination. Large deletion of HSP110 T 17 has been associated with efficacy of adjuvant chemotherapy in dMMR/MSI CRCs. The aim of this study was to evaluate the interest of HSP110 deletion/expression as a diagnostic tool of dMMR/MSI CRCs and a predictive tool of adjuvant chemotherapy efficacy. All patients with MSI CRC classified by molecular testing were included in this multicenter prospective cohort (n = 381). IHC of the 4 MMR proteins was carried out. HSP110 expression was carried out by IHC (n = 343), and the size of HSP110 T 17 deletion was determined by PCR (n = 327). In the 293 MSI CRCs with both tests, a strong correlation was found between the expression of HSP110 protein and the size of HSP110 T 17 deletion. Only 5.8% of MSI CRCs had no HSP110 T 17 deletion (n = 19/327). HSP110 T 17 deletion helped to re-classify 4 of the 9 pMMR/MSI discordance cases as pMMR/MSS cases. We did not observe any correlation between HSP110 expression or HSP110 T 17 deletion size with time to recurrence in patients with stage II and III CRC, treated with or without adjuvant chemotherapy. HSP110 is neither a robust prognosis marker nor a predictor tool of adjuvant chemotherapy efficacy in dMMR/MSI CRC. However, HSP110 T17 is an interesting marker, which may be combined with the other pentaplex markers to identify discordant cases between MMR IHC and MSI.

Reappraisal of HER2 status in the spectrum of advanced urothelial carcinoma: a need of guidelines for treatment eligibility.

Although human epidermal growth factor receptor 2 (HER2) may represent a therapeutic target, its evaluation in urothelial carcinoma of the bladder does not rely on a standardized scoring system by immunohistochemistry or fluorescent in situ hybridization (FISH), as reflected by various methodology in the literature and clinical trials. Our aim was to improve and standardize HER2 amplification detection in bladder cancer. We assessed immunohistochemical criteria derived from 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAPs) guidelines for breast cancer and investigated intratumoral heterogeneity in a retrospective multicentric cohort of 188 patients with locally advanced urothelial carcinoma of the bladder. Immunohistochemistry was performed on 178 primary tumors and 126 lymph node metastases, eligible cases (moderate/strong, complete/incomplete membrane staining) were assessed by FISH. HER2 overexpression was more frequent with 2013 ASCO/CAP than 2007 ASCO/CAP guidelines (p < 0.0001). The rate of positive HER2 FISH was similar between primary tumor and lymph node metastases (8%). Among positive FISH cases, 48% were associated with moderate/strong incomplete membrane staining that were not scored eligible for FISH by 2007 ASCO/CAP criteria. Among 3+ immunohistochemistry score cases, 67% were associated with HER2-positive FISH. Concordance between primary tumors and matched lymph node metastases was moderate for immunohistochemistry (κ = 0.54 (CI 95%, 0.41-0.67)) and FISH (κ = 0.50 (CI 95%, 0.20-0.79)). HER2-positive FISH was more frequent in micropapillary carcinomas (12%) and carcinoma with squamous differentiation (11%) than in pure conventional carcinoma (6%). Intratumoral heterogeneity for HER2 immunohistochemistry was observed in 7% primary tumor and 6% lymph node metastases; 24% positive HER2 FISH presented intratumoral heterogeneity. Our study suggests that HER2 evaluation should include an immunohistochemistry screening step with eligibility for FISH including incomplete/complete and moderate/strong membrane staining. Spatial or temporal intratumoral heterogeneity prompts to perform evaluation on both tumor and lymph node, and for each histological variant observed.

Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial.

BACKGROUND: In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery. METHODS/DESIGN: PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial. TRIAL REGISTRATION: NCT01675999 (ClinicalTrials.gov).

Microbial dysbiosis and colon carcinogenesis: could colon cancer be considered a bacteria-related disease?

Colorectal cancer (CRC) is posing an increasingly important burden on the health care system, with western countries seeing a growing incidence of the disease. Except for germline DNA mutations which have been attributed to less than 5% of patients, little is known about the main causes of CRC. However, environment factors such as food, lifestyle and medication are now suspected to have a major influence on inducing cancers. Today, exhaustive quantitative and qualitative evaluation of all environmental factors is not possible. Various environment-induced diseases have been characterized based on colon microflora, also called microbiota, analyses. Growing data have shown specific changes in microflora (i.e. dysbiosis) in the stools of patients with colon cancer or those adherent to the colonic mucosa. Thus, it appears that microbiota may be considered a platform offering host and environment interactions for studying CRCs. The hypothesis that colon cancer might be a bacteria-related disease is suggested and perspectives are discussed.

Liver resection for colorectal liver metastases with peri-operative chemotherapy: oncological results of R1 resections.

BACKGROUND: Retrospective analysis of outcomes of R0 (negative margin) versus R1 (positive margin) liver resections for colorectal metastases (CLM) in the context of peri-operative chemotherapy. METHODS: All CLM resections between 2000 and 2006 were reviewed. Exclusion criteria included: macroscopically incomplete (R2) resections, the use of local treatment modalities, the presence of extra-hepatic disease and no peri-operative chemotherapy. R0/R1 status was based on pathological examination. RESULTS: Of 86 eligible patients, 63 (73%) had R0 and 23 (27%) had R1 resections. The two groups were comparable for the number, size of metastases and type of hepatectomy. The R1 group had more bilobar CLM (52% versus 24%, P = 0.018). The median follow-up was 3.1 years. Five-year overall and disease-free survival were 54% and 21% for the R0 group and 49% and 22% for the R1 group (P = 0.55 and P = 0.39, respectively). An intra-hepatic recurrence was more frequent in the R1 group (52% versus 27%, P = 0.02) and occurred more frequently at the surgical margin (22% versus 3%, P = 0.01). DISCUSSION: R1 resections were associated with a higher risk of intra-hepatic and surgical margin recurrence but did not negatively impact survival suggesting that in the era of efficient chemotherapy, the risk of an R1 resection should not be considered as a contraindication to surgery.

[Collagenous gastritis and ileo-colitis occurred in autoimmune context: report of a case and review of the literature]. / Gastrite collagène et iléocolite collagène survenant dans un contexte dysimmunitaire: à propos d'un cas et revue de la littérature.

Collagenous colitis belongs to the group of microscopic colitis. The aetiology and pathogenesis are unknown but different pathogenic hypothesis, autoimmune, infectious, alimentary and medicinal being are advanced, the last one being the most frequent aetiology. The collagenous gastritis is a rare entity and its association with collagenous colitis was exceptionally reported, only six cases being published. We report the seventh case of collagenous gastritis, ileitis and colitis in a 75-year-old woman with chronic diarrhea and important weight loss. This thickened subepithelial collagen band was appeared in an autoimmune injury context with antecedent of Hashimoto's thyroiditis and probably chronic atrophic Biermer's gastritis. The clinical and histological evolution was favourable with budesonide.

Hyaline globules (thanatosomes) in gastrointestinal epithelium: pathophysiologic correlations.

Hyaline globules (HGs; thanatosomes) are well-defined morphologic and functional entities representing a degenerative phenomenon common to all cell types. We present the first quantitative and qualitative study of HGs in normal and pathologic gastrointestinal (GI) epithelium from a series of 2,230 biopsies. HGs were very rarely found in normal epithelium (1.1%), but their number increased significantly in specimens with ischemic injury (47%) and benign regenerative proliferation (70%). Their incidence in adenomatous polyps and adenocarcinomas was about 11% to 27%. Of the HGs, 2.9% contained nuclear fragments. Our results entirely support the unifying morphogenetic concept for HGs. The role of 2 obligatory morphogenetic factors for the generation of thanatosomes (propensity to apoptosis and heterophagy/autophagy) is confirmed. The nature of the third factor, ischemic conditions, is specified. Although a nonspecific microscopic phenomenon, HGs in the GI tract represented a relatively constant and useful histologic marker of enhanced cell turnover and ischemic injury.

[Retrospective diagnosis of stromal tumor with liver and nodal metastasis in a hemorrhagic Meckel's diverticulum appearing 8 years after the first resection]. / Diagnostic rétrospectif de tumeur stromale d'un diverticule de Meckel révélée par une hémorragie devant une récidive péritonéale métastatique survenant 8 ans après la résection initiale.

Meckel's diverticulum is the most prevalent congenital abnormality of the gastrointestinal tract (0.3-4%). The gastrointestinal stromal tumours (GIST) are rare tumours. Only few cases of GIST developed in Meckel's diverticulum have been published in the literature. We reported a case of a woman with a diagnosis of GIST of Meckel's diverticulum retrospectively made 8 years after the resection of an haemorrhagic Meckel's diverticulum, whom she developed a large size intra-abdominal tumour with liver and nodes metastasis.

[Single filiform polyp revealed by severe haemorrhage in a patient with normal colon. Report of a case and review of the literature]. / Polype filiforme unique développé dans un côlon normal et révélé par une hémorragie digestive sévère. A propos d'un cas et revue de la littérature.

Filiform polyposis or giant inflammatory polyp is an uncommon benign lesion that has principally been reported in patients with evidence of inflammatory bowel disease, Crohn's disease or ulcerative colitis. It appears to be a sequella of diffuse mucosal inflammation. More rarely, PF found in association with colonic non specific inflammation. PF has rarely been reported in patients without previous colonic disease. We report the case of a 60-year-old woman without history of colonic disease who presented a PF revealed by hematochesia.

[Tropical sprue: two cases in the Paris area]. / Sprue tropicale: à propos de 2 cas observés dans la région parisienne.

Tropical sprue (TS) is a postinfective tropical malabsorption that occurs in tropical countries. TS is associated with a persisting colonization of the small-intestine lumen by enterotoxinogenic bacteria that cause subsequent enterocyte damage affecting all or part of the small-intestine. We report two cases of TS that occurred in inhabitants of Paris area returned from endemic areas. The first observation concerned a 76-year old woman admitted for anorexia, loss of 20 kg and anemia. The second observation concerned a 53-year old man referred for chronic diarrhea and loss of 40 kg within 4 years. In both cases, duodenal lesions consisted of subtotal and total villous atrophy with prominent infiltration of the damaged surface epithelium with lymphocytes and infiltrate of lymphocytes and plasma cells of the lamina propria. The two patients recovered under antibiotics, confirming the diagnosis of TS.

[Sarcomatoid carcinoma of the colon: report of a case and review of the literature]. / Carcinome sarcomatoïde du côlon: présentation d'un cas et revue de la littérature.

Sarcomatoid carcinomas or carcinosarcoma are rare tumors composed of mixed carcinoma cells and mesenchymal cells. Thirteen cases with colorectal involvement have been published to date. We report a case of sarcomatoid carcinoma of the colon in a 67-Year-old woman hospitalized with a history of anemia and bloody stools. The patient underwent a left hemicolectomy. Immunohistochemistry revealed two cell components (undifferentiated carcinomatous and sarcomatous components). The patient died of her tumor 2 Months after the operation. Our review of the literature stresses the poor prognosis associated with colonic sarcomatoid carcinoma.

[Acute cytomegalovirus (CMV) recto-colitis mimicking rectal carcinoma without apparent cause of immunodeficiency]. / Rectite aiguë pseudo-tumorale à cytomégalovirus (CMV) chez l'adulte sans cause apparente d'immunodépression.

Cytomegalovirus (CMV) infection of the gastrointestinal tract occurs mainly in immunosuppressed patients. We report here the case of a 76-Year-old woman, without obvious cause of immunosuppression, who developed severe proctitis. The clinical course was favourable with ganciclovir therapy. In the absence of controlled data in the field of CMV intestinal infections in immunocompetents, we discuss the potential benefit of an antiviral therapy in those patients who do not recover rapidly and spontaneously.

[Isolated ileal villous atrophy: a rare cause of chronic diarrhea. Report of a case and review of the literature]. / Atrophie villositaire iléale isolée primitive: une cause rare de diarrhée chronique. Présentation d'un cas et revue de la littérature.

Villous atrophy of the terminal ileum is usually secondary to celiac disease or other diseases. Very few cases of primary ileal villous atrophy have been reported in the literature. We report here the case of a 37-year-old man with chronic diarrhea since childhood without features of malabsorption. The macroscopic and microscopic appearance of the duodenal, ileal and colonic mucosae at endoscopy and contrast radiography of the small bowel was normal. Ileal lesions consisted of total villous atrophy. Search for antinuclear antibodies, anti-endomysium and anti-gliadin IgA and IgG and HIV serology were negative. Serum immunoglobulin level was normal. Diarrhea resolved under treatment with colestyramine.